Beta-Adrenergic Blockers

Types of adrenoceptors

Alpha-1
Vasoconstriction
Increased peripheral resistance
Increased blood pressure

Alpha-2
Inhibition of norepinepherine release
Inhibition of insulin release

Beta-Blockers

Types of Adrenoceptors

Beta-1

Tachycardia

Increased lipolysis

Increased myocardial contractility

Beta-2

Vasodilation (in skeletal vasculature)

Slightly decreased peripheral resistance

Bronchodilation

Increased muscle and liver glycogenolysis

Increased release of glucagon

Beta-Blockers

Mechanism of Action

All clinically available beta-blockers are competitive

antagonists
Non-selective act on both B1 and B2 receptors
Generally, they antagonize effects of catecholamines on the
heart

Effects of beta blockade

Angina Tx = decreased myocardial oxygen consumption due to

reduced rate and contractility
Hypotensive effect = unclear mechanism
Possibilities: diminished CO, decreased NE release at
postgang. symp. nerve endings, reduced renin

Beta-Blockers

Effects of beta blockade (contd.)

Arrythmia tx = reduces rate of spontaneous depolarization of

sinus node, slows conduction in atria
tx for symptomatic mgmt. of hyperthyroidism by controlling
tachycardias and arrythmias
tx of migrane, aortic dissection

Beta-Blockers

pharm properties

variations in:
cardioselectivity
membrane-stabilizing effects (local anesthesia)
intrinsic sympathomimetic activity (some are partial
agonists)
lipid solubility
these variations are generally of little clinical significance
2 important ones are lipid and agonist properties

Beta-Blockers

lipophilic

hydrophilic

propranolol, metoprolol, oxprenolol, bisoprolol, carevdilol

readily absorbed from GI, metabolized in liver
large volume of distrib, and penetrate BBB well
acebutolol, atenolol, betaxolol, carteolol, nadolol. sotalol
less readily absorbed, not extensively metabolized
long plasma half-lives

= hepatic failure prolong t1/2 lipo, renal failure prolongs

hydrophilic

Beta-Blockers

B-agonist (intrinsic sympathomim. activity = ISA)

pindolol, alprenolol, acebutolol, carteolol, dilevalol, oxprenolol

cause little or no resting heart rate depression, but block
increased rate due to exercise
useful if patient is naturally bradycardic at rest

Beta-Blockers

Cardioselective

metoprolol, esmolol, acebutolol, atenolol, betaxolol

relative selectivity for B1 receptor
theoretically cause less bronchoconstriction and peri
vasodilation
lose selective effects at higher doses

Beta-Blockers

Adverse effects

CNS effects (sedation, depression, hallucinations)

seen with hydrophilic as well as lipophiles
precipitation of heart failure
if patient relies on increased sympathetic drive for cardiac
compensation
aggravation of bronchospasm in asthma
hypoglycemia in diabetes
due to blockade of catecholamine-mediated counterreg and
antagonism of adrenergic warning signs of hypoglycemia)
hyperkalemia if K intolerance
elevation in 3glycerides, depression HDL

Nitrates

Mechanism

cause rapid reduction in myocardial oxygen demand

relax vascular smooth muscle
venous more than arterial
cause intracellular conversion to nitrite ions, and then to
nitric oxide
this activated guanylate cyclase and increases cell GMP
elevated cGMP = dephosphorylation of myosin light chain
= muscle relaxation

Nitrates

Cardiovascular effects

2 major
dilation of large veins, causing pooling of blood
diminishes preload = reduces work of heart
dilates coronary vasculature = increased blood supply
to heart muscle
Adverse
most common is headache especially if recovering from
long-acting agents
high doses
postural hypotension, flushing, tachycardia

Beta-Blockers and NO

Kalinowski, et. al.

Third-Generation -Blockers Stimulate Nitric Oxide
Release From Endothelial Cells Through ATP Efflux

A Novel Mechanism for Antihypertensive Action

Circulation, May 12, 2003

Abstract

3rd generation beta-blockers (like Nebivolol and Carvedilol)

have endothelium-dependent vasodilating properties
specifically related the microcirculation by a molecular
mechanism that is not understood yet
classic beta-blockers dont have this effect

Beta-Blockers and NO

Abstract (contd)

Hypothesized mech:
stimulation of NO release from microvascular endothelial
cells by extracellular ATP
ATP is known to fxn as autocrine and paracrine
signaling factor

Results/Conclusions

Contraction and relaxation of renal glomerular vasculature

were measured, also active NO and extracellular ATP
Results showed that 3rd gen B-Bs induce relaxation of renal
glomerular microvasculature through ATP efflux causing NO
release from GECs.

References

Harrisons, 15th Ed.

Lippincott Pharmacology, 2nd Ed.
Kalinowski et. al., Third-Generation -Blockers
Stimulate Nitric Oxide Release From Endothelial Cells
Through ATP Efflux

Circulation. 2003;107:2747